Wellbutrin XL Mechanism of Action

Pharmacotherapeutic Group: Other antidepressants. ATC Code: N06AX12.
Pharmacology: Pharmacodynamics: Mechanism of Action: Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines (noradrenaline and dopamine) with minimal effect on the re-uptake of indolamines (serotonin) and does not inhibit monoamine oxidase. While the mechanism of action of bupropion, as with other antidepressants, is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
Clinical Trials: Major Depressive Disorder (MDD): The efficacy of bupropion as a treatment for MDD was established with the immediate-release formulation of bupropion in two 4-week, placebo-controlled trials in adult inpatients and in one 6-week, placebo-controlled trial in adult outpatients. In the 1st study, patients were titrated in a bupropion dose range of 300-600 mg/day of the immediate-release formulation on a 3 times daily schedule; 78% of patients received maximum doses of ≤450 mg/day. This trial demonstrated the effectiveness of bupropion on the Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from that scale, and the Clinical Global Impressions (CGI) severity score. A 2nd study included 2 fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and placebo. This trial demonstrated the effectiveness of bupropion, but only at the 450 mg/day dose of the immediate-release formulation; the results were positive for the HDRS total score and the CGI severity score, but not for HDRS item 1. In the 3rd study, outpatients received 300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the effectiveness of bupropion on the HDRS total score, HDRS item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score and the CGI improvement score.
In a longer-term study, outpatients meeting DSM-IV criteria for MDD, recurrent type, who had responded during an 8-week open trial on bupropion (150 mg twice daily of the sustained-release formulation) were randomized to continuation of their same dose of bupropion or placebo, for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator's judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued bupropion treatment experienced significantly lower relapse rates over the subsequent 44 weeks compared to those receiving placebo.
Although there are no independent trials demonstrating the antidepressant effectiveness of Wellbutrin XL, studies have demonstrated similar bioavailability of Wellbutrin XL to both the immediate-release formulation and to the sustained-release formulation of bupropion under steady-state conditions ie, Wellbutrin XL 300 mg once daily was shown to have bioavailability that was similar to that of 100 mg 3 times daily of the immediate-release formulation of bupropion and to that of 150 mg 2 times daily of the sustained-release formulation of bupropion, with regard to both peak plasma concentration (C_max) and extent of absorption, for parent drug and metabolites.
Seasonal Affective Disorder: The efficacy of Wellbutrin XL for the prevention of seasonal major depressive episodes associated with seasonal affective disorder was established in 3 double-blind, placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern (as defined by DSM-IV criteria). Treatment was initiated prior to the onset of symptoms in the autumn (September to November) and was discontinued following a 2-week taper that began the 1st week of spring (4th week of March), resulting in a treatment duration of approximately 4-6 months for the majority of patients. At the start of the study, patients were randomized to receive placebo or Wellbutrin XL 150 mg once daily for 1 week, followed by up-titration to 300 mg once daily. Patients who were deemed by the investigator to be unlikely or unable to tolerate 300 mg once daily were allowed to remain on, or had their dose reduced to, 150 mg once daily. The mean Wellbutrin XL doses in the 3 studies ranged from 257-280 mg/day.
In these 3 trials, the percentage of patients who were depression-free at the end of treatment was significantly higher for Wellbutrin XL than for placebo: 81.4% versus 69.7%, 87.2% versus 78.7% and 84% versus 69% for study 1, 2 and 3, respectively; with a depression-free rate for the 3 studies combined of 84.3% versus 72%.
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination t_½ (±SD) of bupropion after chronic dosing is 21 (±9) hrs and steady-state plasma concentrations of bupropion are reached within 8 days.
In a study comparing 14-day dosing with Wellbutrin XL 300 mg once daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for C_max and AUC for bupropion and the 3 metabolites (hydroxybupropion, threohydrobupropion and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with Wellbutrin XL 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for C_max and AUC for bupropion and the 3 metabolites.
Absorption: Following oral administration of Wellbutrin XL to healthy volunteers, T_max of bupropion are approximately 5 hrs and food did not affect the C_max or AUC of bupropion.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein-binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein-binding of the threohydrobupropion metabolite is about ½ that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three (3) metabolites have been shown to be active: Hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is ½ as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by or which inhibit/induce the cytochrome P450IIB6 (CYP2B6) isoenzyme eg, ritonavir or efavirenz. In a healthy volunteer study, ritonavir at a dose of 100 mg twice daily reduced the AUC and C_max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38% and the erythrohydrobupropion decreased by 48%.
In a 2nd healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the AUC and the C_max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50% and the erythrohydrobupropion decreased by 68%.
In another healthy volunteer study, Kaletra (lopinavir 400 mg/ritonavir 100 mg twice daily) decreased bupropion AUC and C_max by 57%. The AUC and C_max of hydroxybupropion were decreased by 50% and 31%, respectively (see Precautions).
In a study in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduces the AUC and C_max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C_max of hydroxybupropion was increased by 50%.
Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized by this isoenzyme (see Precautions).
In humans, C_max of hydroxybupropion occur approximately 7 hrs after administration of Wellbutrin XL. Following administration of Wellbutrin XL, C_max of hydroxybupropion are approximately 7 times the peak level of the parent drug at steady-state. The elimination t_½ of hydroxybupropion is approximately 20 (±5) hrs and its AUC at steady-state is about 13 times that of bupropion. The T_max for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination t_½ are longer, approximately 33 (±10) and 37 (±13) hrs, respectively and steady-state AUCs are 1.4 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300-450 mg/day.
Elimination: Following oral administration of 200 mg of ¹⁴C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and faeces, respectively. The fraction of the dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity [eg, liver disease, congestive heart failure (CHF), age, concomitant medications, etc] or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose studies, 1 in patients with alcoholic liver disease and 1 in patients with mild to severe cirrhosis. The 1st study showed that the t_½ of hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in 8 healthy volunteers (32±14 hrs vs 21±5 hrs, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53-57%) in patients with alcoholic liver disease. The differences in t_½ for bupropion and the other metabolites in the 2 patient groups were minimal.
The 2nd study showed no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C_max and T_max) and its active metabolites (t_½) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion C_max and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion t_½ was also longer (29 hrs in patients with severe hepatic cirrhosis vs 19 hrs in healthy subjects). For the metabolite hydroxybupropion, the mean C_max was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean C_max was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median T_max was observed 19 hrs later for hydroxybupropion and 31 hrs later for threo/erythrohydrobupropion. The mean t_½ for hydroxybupropion and threo/erythrohydrobupropion were increased 5-fold and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see Dosage & Administration, Warnings and Precautions).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug C_max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A 2nd study, comparing normal subjects and patients with moderate to severe renal impairment (GFR 30.9±10.8 mL/min) showed that exposure to a single 150 mg dose sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced by impaired renal function (see Precautions).
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300-750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18-83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest that there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single- and multiple-dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see Precautions).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150 mg dose of bupropion, there was no statistically significant difference in C_max, t_½, T_max, AUC or clearance of bupropion or its active metabolites between smokers and nonsmokers.